Current therapies used to treat disease (e.g., cancer, infection with microorganisms, etc.) have considerable limitations. For example, current chemotherapeutics used to treat many cancer patients suffer from high toxicity, poor tumor targeting, and multidrug resistance (MDR), which together often result in incomplete destruction of the tumors. These drawbacks prevent effective treatment and are associated with increased morbidity and mortality.
The ability of cancer cells to develop resistance to multiple structurally and functionally non-related cytotoxic drugs, such as multi-drug resistance, is a major barrier to effective chemotherapy and is a critical unmet need. Over the past two decades, numerous researchers across many disciplines have investigated multidrug resistance with the ultimate goal of developing novel P-gp modulators as a way to revert MDR in human cancers. Excitement in this field of drug development is bolstered by several reports documenting many agents, which modulate the function of P-gp are able to restore the cytotoxicity of chemotherapeutic drugs to MDR cells in vitro as well as in experimental tumors in vivo (6). Clinical trials with MDR modulators have also shown some response in tumors that were otherwise non-responsive to chemotherapy (7).
While constitutive P-gp expression in normal healthy tissues is believed to be an important protective mechanism against potentially toxic xenobiotics, during disease states, such as cancer, P-gp is recognized as a major barrier to the bioavailability of administered drugs and thus, resistance to chemotherapy remains an obstacle to the successful treatment of certain cancers (Johnstone et al. (2000), Ho et al. (2003)). Recent chemotherapeutic strategies have integrated the use of hammerhead ribozymes against the MDR1 gene (encodes for P-gp) and MDR1 targeted anti-sense oligonucleotides (Fojo et al., 2003). Yet, despite these advances, all MDR inhibitors in development that have progressed to the stage of clinical trials have been generally ineffective or only effective at highly toxic doses (Baird et al., 2003). In addition, many of these modulators adversely influence the pharmacokinetics and bio-distribution of co-administered chemotherapeutic drugs. Moreover, although siRNA mediated silencing of P-gp is a promising approach, this method may genetically alter cell fate and require delicate constructed delivery systems that has, thus far, hampered its clinic usage.
Despite advances in the field, all MDR inhibitors in development that have progressed to the stage of clinical trials have been widely ineffective or only effective at highly toxic doses (8). Furthermore, since most of the prior art modulators adversely influence the pharmacokinetics and biodistribution of co-administered chemotherapeutic drugs, there remains a need for new, effective MDR and/or P-gp modulators without the undesired side effects (4).